Clinical Impact of New NAFLD/NASH Data From San Francisco 2018

Clinical Impact of New NAFLD/NASH Data From
San Francisco 2018
This program is supported by educational grants from
AbbVie and Gilead Sciences
CCO Independent Conference Coverage*
of The Liver Meeting 2018; November 9-13, 2018; San Francisco, California
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About These Slides
Slide credit: clinicaloptions.com

Faculty
Ira M. Jacobson, MD
Director of Hepatology
Department of Medicine
NYU School of Medicine
New York, New York
Philip N. Newsome, PhD, FRCPE
Professor of Hepatology
University of Birmingham
Birmingham, United Kingdom

Disclosures
Ira M. Jacobson, MD, has disclosed that he has received funds for
research support and consulting fees from AbbVie, Bristol-Myers Squibb,
Enanta, Genfit, Gilead Sciences, Intercept, Janssen, Merck, Novo Nordisk,
Spring Bank, and Trek Therapeutics.
Philip N. Newsome, PhD, FRCPE, has disclosed that he has received
consulting fees from Afimmune, Boehringer Ingelheim, Gilead Sciences,
Intercept, Novo Nordisk, Pfizer, and Shire; has received funds for research
support from Boehringer Ingelheim; and has served on speaker bureaus
for Intercept and Norgine.

Noninvasive Screening for NAFLD/NASH

Detection of Active NASH and Advanced Fibrosis With
FibroScan-Based Scoring
 Prospective, multicenter study of patients undergoing liver biopsy for
suspected NASH (N = 335)
 Score based on fibrosis, steatosis, and inflammation (LSM, CAP, AST)
used to detect patients with active NASH and advanced fibrosis
(NAS ≥ 4, fibrosis level F ≥ 2)
‒ Performance assessed by AUROC
‒ Validated internally by bootstrap
‒ Cutoffs determined in derivation cohort
‒ External validation: French bariatric surgery, Malaysian NAFLD,
US screening cohorts
Sasso. AASLD 2018. Abstr 140. Slide credit: clinicaloptions.com

Validation of Score for Detection of Active NASH and
Advanced Fibrosis
Sasso. AASLD 2018. Abstr 140. Slide credit: clinicaloptions.com
 Good performance in derivation and validation cohorts
‒ In multiple clinical settings (screening, bariatric surgery, NAFLD)
‒ In multiple geographical areas (Asia, Europe, United States)
Derivation Cohort External Validation Cohorts
Characteristic
Development
Population
(N = 335)
Bootstrap
Validation
(N = 335)
Malaysian
NAFLD Cohort
(N = 231)
US Screening
Cohort
(N = 193)
French Bariatric
Surgery Cohort
(N = 110)
All
(N = 534)
NASH, NAS ≥ 4, F ≥ 2
prevalence, n (%)
166 (50) (44-55)* 53 (23) 24 (12) 17 (15) 96 (18)
VCTE + CAP + AST
AUROC (95% CI)
0.83
(0.78-0.87)
0.83
(0.78-0.87)
0.85
(0.80-0.91)
0.91
(0.86-0.96)
0.93
(0.89-0.98)
0.88
(0.85-0.91)
*95% CI for prevalence.

NIS4: Detection of Active NASH and Advanced Fibrosis
With Biomarker-Based Scoring
Sanyal. AASLD 2018. Abstr 142. Slide credit: clinicaloptions.com
 NIS4: score based on biomarkers miR-34a, alpha-2-macroglobulin,
YKL-40, and A1C used to detect patients with active NASH and
advanced fibrosis (NAS ≥ 4, fibrosis level F ≥ 2)
 Baseline data from GOLDEN and RESOLVE-IT trials (N = 714)
‒ Training set: 220 patients from GOLDEN trial
‒ Validation set: first 467 patients screened for inclusion in RESOLVE-IT

Validation of NIS4 for Detection of Active NASH and
Advanced Fibrosis
 For overall population, NIS4 AUROC = 0.83 (95% CI: 0.80-0.86)
‒ Consistently good performance across the clinical spectrum of NAFLD,
regardless of obesity, metabolic syndrome, T2DM status, or sex
Sanyal. AASLD 2018. Abstr 142. Slide credit: clinicaloptions.com
Group Subgroup n
Prevalence
NAS ≥ 4 and F ≥ 2, %
AUC
(95% CI)
Obesity BMI ≤ 30 224 45 0.794 (0.733-0.849)
BMI > 30 490 54 0.838 (0.804-0.873); P = .204
Diabetes No 439 44 0.830 (0.790-0.867)
Yes 275 61 0.801 (0.748-0.854); P = .382
Age ≤ 55 yrs 361 42 0.804 (0.758-0.848)
> 55 yrs 353 59 0.833 (0.791-0.871); P = .358
Sex Female 369 50 0.841 (0.802-0.881)
Male 345 51 0.813 (0.767-0.855); P = .345

Sequential Algorithms to Detect Advanced Fibrosis due
to NASH
 Study of baseline data from
STELLAR trials (N = 3202) to
determine performance of
sequential combinations of
noninvasive tests in diagnosing
F3/F4 liver fibrosis
 Liver biopsy assessment
‒ 41% fibrosis stage F4 (n = 1283)
‒ 30% fibrosis stage F3 (n = 979)
 Algorithm based on noninvasive
tests used low cutoff for
sensitivity (to rule in F0-F2) and
high cutoff for specificity (to
rule in F3/F4)
‒ Novel cutoffs from STELLAR
study: FIB-4 (1.23, 2.10), ELF
(9.35, 10.24), FibroScan (9.6,
14.53 kPa)
‒ Published cutoffs: FIB-4 (1.30,
2.67), ELF (9.8, 11.3), FibroScan
(9.9, 11.4 kPa)
Younossi. AASLD 2018. Abstr LB-10. Slide credit: clinicaloptions.com

Sequential Algorithms to Detect Advanced Fibrosis due
to NASH: Results
 Single tests (either FIB-4, ELF, or FibroScan) led to up to 50%
indeterminate results
 Algorithm using 3 sequential tests (FIB-4, then ELF, then FibroScan) led
to 9% to 10% indeterminate results
Younossi. AASLD 2018. Abstr LB-10. Slide credit: clinicaloptions.com
Outcome, % (95% CI)
Test Cutoffs F3/F4, % Sensitivity Specificity PPV NPV Indeterminate Misclassified
Novel cutoffs
(n = 639)
71 75 (71-79) 82 (76-87) 91 (88-94) 58 (52-64) 9 (7-11) 23 (20-26)
Published cutoffs
(n = 639)
71 64 (60-69) 93 (88-96) 95 (92-97) 52 (46-57) 10 (7-12) 28 (24-31)

Clinical Outcomes
in Patients With NAFLD/NASH

NAFLD Prevalence in Lean vs Obese Adults With or
Without Metabolic Abnormalities
Slide credit: clinicaloptions.com
 Study of adults in NHANES III from 1988-1994 followed through 2011
‒ Obese defined as BMI > 30 and high waist circumference
(> 102 cm for men, > 88 cm for women)
‒ Lean defined as BMI < 25 and normal waist circumference
(≤ 90 cm for men, ≤ 80 cm for women)
Golabi. AASLD 2018. Abstr 179.
NAFLD Prevalence, % All
Obese
(n = 2952)
Lean
(n = 3242)
All patients 19.6 39.4 7.7
Any metabolic abnormalities 18.1 38.4 5.5
No metabolic abnormalities 1.5 1 2.2

Lean, Metabolically Normal Adults With NAFLD:
Mortality
Characteristic Deaths, n
Unadjusted
Mortality, % (95% CI)
P
Value*
Age-Adjusted Mortality,
% (95% CI)
P
Value*
Deaths among lean patients with
NAFLD
 Without metabolic abnormalities
 With metabolic abnormalities
57
8
49
13.83 (8.80 to 18.86)
8.72 (-0.37 to 17.81)
16.60 (11.16 to 22.03)
NA
NA
.1459
18.32 (12.09 to 24.56)
15.01 (3.09 to 26.92)
19.90 (13.19 to 26.61)
NA
NA
.4399
CV deaths among lean patients with
NAFLD
 Without metabolic abnormalities
 With metabolic abnormalities
13
0
13
2.89 (9.14 to 4.87)
0
4.46 (1.79 to 7.13)
NA
NA
.0020
3.71 (1.76 to 5.66)
0
3.71 (1.73 to 5.69)
NA
NA
.0005
*vs lean adults without metabolic abnormalities.
 In lean NAFLD adults without any component of metabolic syndrome,
no increased overall or CV-related mortality vs lean non-NAFLD
controls
‒ Median follow up: 18.9 yrs
Golabi. AASLD 2018. Abstr 179. Slide credit: clinicaloptions.com

Poorer Patient-Reported Outcomes in NASH and With
More Advanced Fibrosis
Younossi. AASLD 2018. Abstr 1683. Slide credit: clinicaloptions.com
Design
 Analysis of NASH patients with bridging
fibrosis or compensated cirrhosis (NASH CRN
stages F3-F4) enrolled in phase III STELLAR
trial evaluating ASK1 inhibitor selonsertib
(N = 1667)
 PROs collected before treatment initiation
‒ Chronic Liver Disease Questionnaire (CLDQ
NAFLD-NASH)
‒ EQ-5D
‒ Short Form-36 (SF-36)
‒ Work Productivity and Activity Index
(WPAI:SHP)
Results
 Physical health–related PROs significantly
worse with NASH patients vs population
norms (all P < .05)
 F4 cohort had significantly poorer PROs vs F3
in most questionnaire components (P < .02)
‒ Average impairment difference for F4 vs F3
across all PROs: -1.6% to -4.7% (P < .05)
‒ Most pronounced impairment in CLDQ
NAFLD-NASH’s Activity and Worry domains

Independent Predictors of Poorer Patient-Reported
Outcomes in NASH
Younossi. AASLD 2018. Abstr 1683. Slide credit: clinicaloptions.com
Independent Predictors of
Poorer Scores in NASH Patients*
Beta, % of PRO
Range Size
Age, per yr 0.15 to 0.53
Male sex 2.1 to 9.8
Black vs white -14.9 to -7.8
Asian vs white 4.3 to 10.2
US enrollment 3.2 to 10.2
Current smoker -7.1 to -3.7
BMI, per kg/m2 -0.80 to -0.18
Diabetes mellitus -4.6 to -3.1
Asthenic conditions -7.5 to -6.1
GI disorders -7.3 to -2.8 *All P < .01 after stepwise selection in multiple models.
Independent Predictors of
Poorer Scores in NASH Patients*
Beta, % of PRO
Range Size
Musculoskeletal and connective
tissue disorders
-11.6 to -2.4
Nervous system disorders -5.7 to -2.7
Psychiatric disorders -13.3 to -4.9
Albumin, per g/dL 4.7 to 10.9
Apolipoprotein A1, per mg/dL 0.05 to 0.07
CRP, per mg/dL -3.2 to -2.0
Haptoglobin, per mg/dL -0.03 to -0.02
A1C, per % -2.2 to -1.4

Bariatric Surgery in Patients With Cirrhosis, Including
NASH Cirrhosis
 Single-center, longitudinal study of patients with compensated or
decompensated cirrhosis (N = 60,543)
Griffin. AASLD 2018. Abstr 218. Slide credit: clinicaloptions.com
Patient Characteristic, %
Cirrhosis With Bariatric Surgery
(n = 292)
Cirrhosis Without Bariatric Surgery
(n = 29,987)
Female 73 38
NASH cirrhosis 16 3
Alcoholic cirrhosis 31 31
Decompensated cirrhosis 71 72

Lower Survival With Bariatric Surgery in Patients With
Cirrhosis, Including NASH Cirrhosis
 Bariatric surgery also a predictor of mortality among compensated and decompensated
cirrhotic patients (obesity not significant)
‒ HR: 1.3; 95% CI 1.12-1.62; P = .002
Slide credit: clinicaloptions.comGriffin. AASLD 2018. Abstr 218.
0
20
40
60
80
Survival(%)
57.9
62.8
100
Patients With Bariatric Surgery Patients Without Bariatric Surgery
P < .04
5-Yr Survival Among Patients With Cirrhosis

Bariatric Surgery and Regression of NASH Fibrosis
 Multicenter, prospective study of long-term impact of bariatric surgery in morbidly
obese NASH patients (N = 190)
Lassally. AASLD 2018. Abstr 70. Slide credit: clinicaloptions.com
Patient Characteristic Patients
Median age, yrs (IQR) 46.5 (38.3-54.3)
Female, % 65.8
Median BMI (IQR) 46.9 (42.9-52.3)
Median ALT (IQR) 45 (32-62)
Median γGT (IQR) 53.5 (35-86.8)
Median A1C, mmol/mol (IQR) 6.9 (5.9-8.8)
Median liver fat amount, % (IQR) 60 (40-75)
Median NAS (IQR) 5 (4-5)
Median Score Patients, %
Brunt activity score
 Mild (1)
 Moderate (2)
 Severe (3)
68.95
23.68
23.68
METAVIR fibrosis score
 F0
 F1
 F2
 F3
 F4
37.36
30.77
16.46
11.54
3.85

Disappearance of NASH and Regression of Fibrosis
Following Bariatric Surgery
 NASH disappearance in 85% of
patients at Yrs 1 and 5
 Fibrosis by Brunt and METAVIR
score significantly reduced at
Yrs 1 and 5 vs baseline
 Patients without fibrosis
regression experienced less
weight loss, higher insulin
resistance (HOMA-IR), and
higher NAS following surgery
Lassally. AASLD 2018. Abstr 70. Slide credit: clinicaloptions.com
METAVIR
Fibrosis Stage
Patients, %
BL Yr 1 Yr 5
F0 37.36 45.69 63.49
F1 30.77 30.17 22.22
F2 16.48 12.93 3.17
F3 11.54 9.48 9.52
F4 3.85 1.72 1.59
P = .01 baseline vs Yr 1; P = .003 Yr 1 vs Yr 5.

Cirrhosis and HCC Risk: Association With Steatosis
and ALT
 Retrospective study of adults with > 1 ALT test and abdominal imaging within
VA hospital system (N = 78,892)
‒ Excluded patients with:
‒ Cirrhosis or HCC before or within 1 yr of first ALT test
‒ HCV or HBV infection
‒ Excessive alcohol use
‒ Rare hepatic conditions (including Wilson’s disease, primary biliary cirrhosis,
primary sclerosing cholangitis, autoimmune hepatitis, or hereditary
hemochromatosis)
 Subjects followed to end of 2015 or to HCC, cirrhosis, or death
Natarjan. AASLD 2018. Abstr 143. Slide credit: clinicaloptions.com

Characteristic No Steatosis, Normal ALT Steatosis, Normal ALT Steatosis, High ALT
Age, mean (SD) 58.1 (10.7) 56.4 (10.3) 53.3 (12.1)
Male, n (%) 22,711 (92.2) 10,478 (91.8) 39,664 (92.6)
Race/ethnicity, n (%)
 White
 Black
 Hispanic
 Other
16,062 (65.2)
4719 (19.2)
1078 (4.4)
483 (2.0)
7532 (66.0)
1752 (15.4)
850 (7.5)
271 (2.4)
30,404 (71.0)
4061 (9.5)
3512 (8.2)
1362 (3.2)
BMI, n (%)
 < 30
 ≥ 30
15,539 (63.1)
9097 (36.9)
5188 (45.5)
6221 (54.5)
15,298 (35.7)
25,748 (64.3)
Comorbidity, n (%)
 DM
 Hypertension
 Dyslipidemia
 CAD
6363 (25.8)
17,794 (72.2)
16,317 (66.2)
5538 (22.5)
3867 (33.9)
8576 (75.2)
8135 (71.3)
2588 (22.7)
14,490 (33.8)
31,467 (73.4)
30,524 (71.2)
8273 (19.3)
Healthcare use, n (%) 21,987 (89.2) 10,340 (90.6) 40,430 (94.4)
Baseline Characteristics

Outcome
Cirrhosis HCC
Patients,
n
Incidence,
n
Follow-up,
PYs
Adjusted Risk
(95% CI)
Incidence,
n
Follow-up,
PYs
Adjusted Risk
(95% CI)
No steatosis,
normal ALT
24,638 445 184,591 Ref 18 186,484 Ref
Steatosis,
normal ALT
11,409 225 343,688 1.1 (1.0-1.3) 9 91,542 1.0 (0.3-3.0)
Steatosis,
high ALT
42,845 1694 90,388 2.2 (2.0-2.5) 117 350,398 3.8 (1.9-7.4)
Risk of Cirrhosis and HCC in Patients With Steatosis and
Normal ALT
Cumulative Incidence/1000 PYs
(95% CI)
No Steatosis,
Normal ALT
Steatosis,
Normal ALT
Steatosis,
High ALT
Cirrhosis 2.41 (2.19-2.65) 2.16 (2.18-2.84) 4.93 (4.70-5.17)
HCC 0.1 (0.06-0.15) 0.1 (0.05-0.19) 0.33 (0.28-0.40)

Phase II Data on Investigational NAFLD/NASH Therapies
Presented at AASLD 2018
Agent MOA N Study Population
GS-9674[1] FXR agonist 140 NASH
Obeticholic acid[2] FXR agonist 84 NASH, fibrosis
Tropifexor[3] FXR agonist 198 NASH
NGM282[4,5] FGF19 analogue 38, 85 NASH
MGL-3196[6] THR-β agonist 125 NASH, hepatic fat fraction ≥ 10%
VK2809[7] THR-β agonist 35 NAFLD, liver fat > 8%, elevated LDL-C and TG
GS-0976[8] ACC inhibitor 75 NASH, no cirrhosis
Aramchol[9] SCD1 inhibitor 247 NASH, overweight or obesity, prediabetes or diabetes
Semaglutide[10] GLP-1 receptor agonist 957 Obesity, no diabetes
1. Patel. AASLD 2018. Abstr 736. 2. Halegoua-De Marzio. AASLD 2018. Abstr 71. 3. Sanyal. AASLD 2018. Abstr LB-23. 4. Harrison. AASLD 2018.
Abstr 104. 5. Paredes. AASLD 2018. Abstr LB-22. 6. Harrison. AASLD 2018. Abstr 14. 7. Loomba. AASLD 2018. Abstr LB-4. 8. Charlton. AASLD
2018. Abstr 1741. 9. Ratziu. AASLD 2018. Abstr LB-5. 10. Newsome. AASLD 2018. Abstr 105. Slide credit: clinicaloptions.com

GS-9674 in Patients With NASH
 Randomized, placebo-controlled phase II study
‒ GS-9674: FXR agonist
Patel. AASLD 2018. Abstr 736. Slide credit: clinicaloptions.com
Patients with MRI-PDFF ≥ 8% and
MRE ≥ 2.5 kPa or biopsy consistent with
NASH and F1-3 fibrosis; no cirrhosis
(N = 140)
GS-9674 30 mg PO QD
(n = 56)
Placebo PO QD
(n = 28)
GS-9674 100 mg PO QD
(n = 56)
Wk 24


 In treated patients with ≥ 30% relative reduction in liver fat, markers of fibrosis also
improved (ELF, TIMP-1, PIINP)
GS-9674 in Patients With NASH: Efficacy
GS-9674
Median Relative
Change in Liver
Enzymes at
Wk 24, % Placebo 30 mg 100 mg
P Value
(100 mg
vs
Placebo)
ALT -6 -19 -18 .11
AST -5 -9 -15 .48
GGT -4 -19 -37 < .001
ALP -4 +5 +18 < .001
GS-9674
Change in Liver
Fat Content from
BL, % Placebo 30 mg 100 mg
P Value
(100 mg
vs
Placebo)
Relative change
 Wk 12
 Wk 24
0
1.9
-7.9
-1.8
-15.0
-22.7
.01
.003
Pts with ≥ 30%
relative
reduction
 Wk 12
 Wk 24
0
12.5
19.2
14.0
30.9
38.9
< .001
.01

GS-9674: Safety at Wk 24
 No change in serum lipids LDL-C, HDL-C, triglycerides, or markers of insulin
resistance (glucose, insulin, A1C, HOMA-IR)
Patients, n (%)
Placebo
(n = 28)
GS-9674
30 mg
(n = 56)
GS-9674
100 mg
(n = 56)
TEAE
 Grade 3/4
19 (68)
1 (4)
43 (77)
5 (9)
50 (89)
3 (5)
Serious TEAE
 Treatment related
1 (4)
0
2 (4)
0
2 (4)
0
Treatment
discontinuation for TEAE
2 (7) 5 (9) 1 (2)
Death 0 0 0
Grade 3/4 lab
abnormality
5 (18) 7 (12) 9 (16)
Patients With Grade
≥ 2 TEAE, n (%)
Placebo
(n = 28)
GS-9674
30 mg
(n = 56)
GS-9674
100 mg
(n = 56)
Pruritus 1 (4) 2 (4) 8 (14)
Hypertension 0 1 (2) 3 (5)
Abdominal pain 0 0 2 (4)
Bronchitis 0 3 (5) 2 (4)
Diarrhea 0 0 2 (4)
Myalgia 0 0 2 (4)
UTI 1 (4) 0 1 (2)
Chest pain 1 (4) 0 0
Dyspepsia 1 (4) 0 0

CONTROL: Obeticholic Acid in Patients With NASH
 Double-blind, placebo-controlled,
phase II study
‒ Obeticholic acid: FXR agonist
 Through Wk 16, patients with vs
without cirrhosis (F4 vs F1-F3)
showed no trend for differences in:
‒ ALT
‒ Bilirubin
‒ Platelets
‒ INR
‒ Change in C4 from baseline
Halegoua-De Marzio. AASLD 2018. Abstr 71. Slide credit: clinicaloptions.com
Adults with NASH,
F1-F4 fibrosis,
without hepatic
decompensation
(N = 84)
Obeticholic Acid 5 mg/day*
(n =20)
(n = 22)
(n = 21)
Placebo*
(n = 21)
Wk 16
*Plus atorvastatin 10 mg Wk 4 through Wk 8, then 20 mg through Wk 12,
then titrated up or down depending on clinical signs until Wk 16

CONTROL: Safety at Wk 16
Halegoua-De Marzio. AASLD 2018. Abstr 71. Slide credit: clinicaloptions.com
F1-F3 F4
Obeticholic Acid* Obeticholic Acid*
Patients, n (%)
Placebo
(n = 17)
5 mg
(n = 16)
10 mg
(n = 14)
25 mg
(n = 15)
Placebo
(n = 4)
5 mg
(n = 4)
10 mg
(n = 7)
25 mg
(n = 7)
TEAEs
 Pruritus
 Muscle spasms
 Diarrhea
 Headache
13 (76)
1 (6)
0
3 (18)
1 (6)
14 (88)
1 (6)
1 (6)
1 (6)
3 (19)
9 (64)
1 (7)
3 (21)
0
0
13 (87)
8 (53)
0
2 (13)
1 (7)
4 (100)
0
0
0
0
4 (100)
0
1 (25)
1(25)
0
5 (71)
1 (14)
0
0
0
7 (100)
4 (57)
1 (14)
0
0
Serious AEs
 Treatment
related
0
0
0
0
0
0
0
0
0
0
2† (50)
0
1‡ (14)
0
1§ (14)
0
*Doses are per day. †Breast cancer stage IV (n = 1) and hypertensive crisis (n = 1). ‡Cholecystitis. §Angioedema.

FLIGHT-FXR: Tropifexor (TXR) in Patients With NASH
 FLIGHT-FXR: 3-part randomized, placebo-controlled,
double-blind, dose-ranging phase IIb study
‒ TXR: FXR agonist
 Current analysis reports pooled
data from Parts A and B
‒ Part C (not shown) ongoing
Sanyal. AASLD 2018. Abstr LB-23. Slide credit: clinicaloptions.com
Part A
Adults with NASH*, weighing
40-150 kg with liver fat ≥ 10%
by MRI-PDFF
(N = 77)
TXR 10 μg QD (n = 14)
Wk 12
TXR 30 μg QD (n = 16)
TXR 60 μg QD (n = 16)
TXR 90 μg QD (n = 15)
Placebo QD (n = 16)
Part B
Adults with NASH*, weighing
40-150 kg with liver fat ≥ 10%
by MRI-PDFF
(N = 121)
TXR 60 μg QD (n = 21)
TXR 90 μg QD (n = 70)
Placebo QD (n = 30)
*NASH defined as F1-F3 on biopsy obtained within 2 yrs of randomization, no other chronic liver disease, with
elevated ALT; or by phenotype (elevated ALT, BMI ≥ 27 in non-Asians or ≥ 23 in Asians, with T2DM).
Efficacy
endpoints
Safety
endpoints

Efficacy of TXR in Overall Population and in Subgroup of
Patients With Biopsy-Proven NASH at Wk 12
 AEs similar among arms; TXR well tolerated with few grade 3/4 AEs or SAEs
‒ 9% of pts on TXR 90 μg QD discontinued or reduced dose for AEs
‒ TXR associated with mild dose-related rise in LDL-C and mild reduction in HDL-C
Sanyal. AASLD 2018. Abstr LB-23. Slide credit: clinicaloptions.com
Relative Change
vs BL,* % (n)
Biopsy-Proven NASH Only Phenotypic and Biopsy-Proven NASH
Placebo
(n = 18)
TXR 60 μg
(n = 12)
TXR 90 μg
(n = 35)
Placebo
(n = 46)
TXR 60 μg
(n = 37)
TXR 90 μg
(n = 85)
FGF19 +46 (12) +232 (10) +556 (34) + 37 (37) + 319 (34) +528 (74)
ALT -15.5 (17) -23.7 (12) -26.9 (32) -15.5 (45) -21.2 (36) -24.0 (73)
GGT -10.5 (17) -46.5 (12) -56.5 (34) -9.2 (45) -43.3 (36) -56.6 (78)
Liver fat content
by MRI-PDFF
-1.8 (14) -7.2 (12) -12.5 (28) -9.8 (41) -16.9 (36) -15.6 (63)
*Change in ALT, GGT, HFF reported as geometric mean of relative change at Wk 12 vs BL, FGF19 as 4 hrs post-dose vs pre-dose at Wk 6.

NGM282 in Patients With NASH
 Multicenter, dose-finding phase II study of NGM282
‒ NGM282: FGF19 analogue
Harrison. AASLD 2018. Abstr 104. Slide credit: clinicaloptions.com
Patients with biopsy-confirmed
NASH, NAS ≥ 4*, stage 1-3 fibrosis,
liver fat ≥ 8% by MRI-PDFF
(N = 43)
*≥ 1 point in each component of NAS.
NGM282
1 mg SC QD†
Followed through
Wk 18
Wk 12
NGM282
3 mg SC QD†
†Option for rosuvastatin 20 mg at
Wk 2 if 10 mg/dL LDL-C increase
observed; titrated up to 40 mg in
Wks 4-8 if LDL-C remained above BL.

NGM282: Liver Fat Content by MRI-PDFF at Wk 12
Change in Liver Fat Content From BL, %
NGM282 1 mg*
(n = 24)
NGN282 3 mg*
(n = 19)
Absolute change -10.9 -11.2
 ≥ 5% absolute reduction 92 100
 Normalized LFC† 33 63
Relative change -57 -67
 ≥ 30% relative reduction 92 100
*All absolute and relative changes P < .001 vs baseline.
†Normalized LFC defined as absolute MRI-PDFF ≤ 5%.

 Patients with NASH resolution (n = 19): 16%  Patients with NASH resolution (n = 19): 11%
NGM282: Fibrosis at Wk 12
NGM282 1 mg NGM282 3 mg
Fibrosis Stage at Baseline
Patients, % (n = 24)
16%
42%
38%
4%
F1
F2
F3
F4
Fibrosis Response at Wk 12
Patients, %
25%
58%
17%
Improved
Worsened
No Change
Fibrosis Stage at Baseline
Patients, % (n = 19)
16%
26%
53%
5%
F1
F2
F3
F4
Fibrosis Response at Wk 12
Patients, %
42%
47%
11%
ImprovedWorsened
No Change

NGM282: Safety
All Adverse Events
 No new safety signals observed;
most events were mild or resolved
on treatment
Gastrointestinal Events
 Most common treatment-emergent
adverse event was mild
gastrointestinal symptoms consisting
of nausea and loose, frequent stools
 2 patients discontinued due to
diarrhea
 Gastrointestinal symptoms improved
by separating dosing from mealtimes
and reducing meal size
Patients, n
NGM282
1 mg
NGM282
3mg
Serious adverse events
• Treatment related
1*
0
4†
0
*Renal mass.
†Cardiac arrest (nonmyocardial infarction), chest
pain (musculoskeletal), pleurisy, pneumonia.

VK2809 in Patients With NAFLD
 Randomized, multicenter, placebo-controlled phase IIa study
‒ VK2809: THR-β agonist
Loomba. AASLD 2018. Abstr LB-4. Slide credit: clinicaloptions.com
Patients with NAFLD, liver
fat > 8% by MRI-PDFF, LDL-C
> 110 mg/dL, triglycerides
≥ 120 mg/dL
(N = 47)
VK2809 10 mg QD
(n = 16)
Placebo
(n = 15)
VK2809 10 mg QOD
(n = 16)
Wk 12
Open-label
follow up to Wk 16

VK2809: Liver Fat Content by MRI-PDFF at Wk 12
Change in Liver Fat Content
From BL to Wk 12
VK2809
Placebo
(n = 11)
10 mg QOD
(n = 13)
10 mg QD
(n = 11)
Mean absolute change, % (SD)
 P value vs placebo
-0.9 (2.8) -8.9 (6.2)
.011
-10.6 (5.2)
.0025
Median relative change, %
-8.9 -56.5
.0014
-59.7
.0003
Pts with ≥ 30% relative reduction, %
18.2 76.9
.012
90.9
.0019

VK2809: Lipids, Safety at Wk 12
Wk 12 Safety Outcomes, n
VK2809
Placebo
(n = 11)
10 mg QOD
(n = 13)
10 mg QD
(n = 11)
AEs 36 21 31
Serious AEs 0 0 0
 VK2809 also associated with significant decreases in Lp(a), ApoB
Wk 12 Placebo-Adjusted Change in LDL-C
VK2809
10 mg QOD
(n = 15)
10 mg QD
(n = 16)
Overall
(n = 31)
% change from BL -23.6 -20.2 -21.8
P value .0121 .0269 .0061

MGL-3196 in Patients With NASH
 Multicenter, randomized, double-blind, placebo-controlled phase II trial
‒ MGL-3196: THR-β agonist
*20-mg dose adjustment up or down
allowed at Wk 4.
Patients with biopsy-confirmed
NASH, NAS ≥ 4, F1-3 fibrosis, ≥ 10%
liver fat by MRI-PDFF
(N = 125)
MGL-3196 80 mg PO QD*
(n = 84)
Placebo PO QD
(n = 41)
Wk 36
Primary Endpoint
Wk 12
Open-label
extension study

MGL-3196: Efficacy at Wks 12, 36
 Ongoing open-label extension suggests improvements of change in liver fat content are maintained
*P < .0001 vs placebo.
Reduction in Fibrosis Score ≥ 1 Point, % Placebo MGL-3196 P Value
Second harmonic generation score 12 32 .03
Pathology score 23 29 NS
MGL-3196*
Change in Liver Fat Content, %
Placebo
(n = 38)
All Patients
(n = 78)
High Exposure
(n = 44)
Wk 12 Wk 36 Wk 12 Wk 36 Wk 12 Wk 36
Relative -10 -8 -36 -37 -42 -49
Absolute -1.6 -2.3 -7.6 -8.5 -8.8 -9.4
≥ 30% relative reduction 18 30 60 68 75 77
Liver Fat Content by MRI-PDFF
Fibrosis at Wk 36

MGL-3196: Efficacy at Wks 12, 36
 Ongoing open-label extension suggests improvements of change in liver fat content are maintained
*P < .0001 vs placebo.
Change in Fibrosis or NASH by Biopsy, % Placebo MGL-3196 P Value
Reduction in Fibrosis Score ≥ 1 Point
 Second harmonic generation score
 Pathology score
12
23
32
29
.03
NS
Resolution of NASH 6 27 .02
MGL-3196*
Change in Liver Fat Content by
MRI-PDFF, %
Placebo
(n = 38)
All Patients
(n = 78)
High Exposure
(n = 44)
Wk 12 Wk 36 Wk 12 Wk 36 Wk 12 Wk 36
Relative -10 -8 -36 -37 -42 -49
Absolute -1.6 -2.3 -7.6 -8.5 -8.8 -9.4
≥ 30% relative reduction 18 30 60 68 75 77

MGL-3196: Lipids, Safety
Lipids Safety
 AEs generally mild and balanced
between groups, except increase in
loose stools at beginning of
treatment, usually 1 episode
‒ Some AEs moderate
 Laboratory abnormalities balanced
between groups
 Serious AEs (n = 7) balanced between
groups with none related to
treatment
Change in Lipids
From BL to Wk 36 % Change P Value
LDL-C -22.3 < .0001
ApoB -21.9 < .0001
Triglycerides -36 < .0001
Lp(a) -36.8 < .001
ApoCIII -36.5 < .0001

ARREST: Aramchol in Patients With NASH and Diabetes
or Prediabetes
 Randomized, global phase IIb study
‒ Aramchol: SCD1 modulator
‒ 60% with stage 2/3 fibrosis; 70% with NAS ≥ 5 at BL
Ratziu. AASLD 2018. Abstr LB-5. Slide credit: clinicaloptions.com
Adults with diabetes or
prediabetes, biopsy-confirmed
NASH, NAS ≥ 4, MRS > 5.5%,
(N = 247)
Aramchol 400 mg QD
(n = 101)
Placebo
(n = 48)
Aramchol 600 mg QD
(n = 98)
Wk 52
Follow up to Wk 65

ARREST: Efficacy at Wk 52
 Aramchol 600 mg also associated with improvement in ALT, AST, A1C
vs placebo
Aramchol
Wk 52 Outcome, % (n/N) Placebo 400 mg 600 mg
P Value
(600 mg vs
Placebo)
≥ 5% absolute reduction in liver fat by MRI 24.4 (10/41) 36.7 (33/90) 47 (39/93) .0279
Resolution of NASH without worsening fibrosis 5 (2/40) 7.5 (6/80) 16.7 (13/78) .051
≥ 1 stage fibrosis improvement without worsening
NASH
17.5 (7/40) 21.3 (17/80) 29.5 (23/78) .211

ARREST: Safety at Wk 52
Patients
Placebo
(n = 48)
Aramchol 400 mg
(n = 101)
Aramchol 600 mg
(n = 98)
Discontinuation for AEs, % 4.2 3 4.1
Serious AEs, %
 Deaths
12.5
0
8.9
0
9.2
0
AE, % (n)
 Constipation
 Cough
 Fatigue
 Headache
 Influenza
 Nausea
 Pruritus
 UTI
12.5 (6)
8.3 (4)
8.3 (4)
12.5 (6)
4.2 (2)
12.5 (6)
6.3 (3)
6.3 (3)
5 (5)
4 (4)
7.9 (8)
13.9 (14)
7.9 (8)
9.9 (10)
6.9 (7)
14.9 (15)
8.2 (8)
5.1 (5)
3.1 (3)
15.3 (15)
5.1 (5)
9.2 (9)
11.2 (11)
13.3 (13)

Semaglutide in Obese Patients With No Diabetes
 Post hoc analysis of multicenter, randomized, double-blind phase II trial
Newsome. AASLD 2018. Abstr 105. Slide credit: clinicaloptions.com
Adults with BMI ≥ 30,
≥ 1 unsuccessful attempt at
weight loss, no diabetes
(N = 957)
Semaglutide .05 mg QD escalated Q4W* (n = 103)
Wk 52
Placebo* (n = 136)
Current
post hoc analysis
*Plus diet of -500 kcal/day and increased physical activity.
Liraglutide 3 mg QD escalated QW* (n = 103)

Semaglutide in Obese Patients With No Diabetes:
Baseline Characteristics
BL Characteristic
With Elevated BL ALT
(n = 499)
Without Elevated BL ALT
(n = 458)
Age, yrs (range) 48 (18-76) 47 (19-86)
Male, n (%) 187 (37.5) 151 (33.0)
Weight, kg (range) 106.9 (70.5-216.3) 107.8 (70.2-243.7)
BMI (range) 37.4 (29.7-77.1) 37.9 (29.7-80.3)
A1C, % (range) 5.5 (4.3-6.6) 5.5 (4.2-7.0)
Lipids, mmol/L (range)
 Total cholesterol
 LDL cholesterol
 HDL cholesterol
 Triglycerides
5.2 (2.7-9.7)
3.2 (1.1-6.2)
1.2 (0.5-2.4)
1.6 (0.5-11.9)
5.0 (2.6-10.3)
3.0 (0.8-7.2)
1.3 (0.7-2.9)
1.4 (0.4-9.9)
Liver enzymes, IU/L (range)
 ALT
 AST
34 (20-313)
24 (12-272)
17 (3-30)
16 (8-62)
Impaired fasting glucose (≥ 6.1 mmol/L), n/N (%) 76/499 (15.2) 57/457 (12.5)
*Elevated ALT defined as > 30 IU/L for men, > 19 IU/L for women.

Semaglutide in Obese Patients With Elevated ALT and
No Diabetes: Change in ALT Through 52 Wks
MeanALTRatiotoBaseline
Semaglutide 0.05 mg
Semaglutide 0.1 mg
Semaglutide 0.2 mg
Semaglutide 0.3 mg
Semaglutide 0.4 mg
Placebo
Wk 4 Wk 16 Wk 28 Wk 40 Wk 52
0.7
0.8
0.9
1.0
1.1
1.2

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